Reactions of α-hydroxyketene dithioacetals with Lawesson's reagent: An efficient method for the synthesis of α,β-unsaturated dithioesters

Article abstract of DOI:10.1055/s-2005-865301

The α-hydroxyketene dithioacetals 2 and 5, obtained from α-oxoketene dithioacetals by the 1,2-reduction or the 1,2-addition of carbon nucleophiles, on treatment with Lawesson's reagent afforded α,β-unsaturated dithioesters 3 and 6 in good yields. Georg Th

Full text of DOI:10.1055/s-2005-865301

PAPER
1261
Reactions of a-Hydroxyketene Dithioacetals with Lawesson’s Reagent:
An Efficient Method for the Synthesis of a,b-Unsaturated Dithioesters
Reactions of
a
a
-
Hydroxyk
t
D
h
ithioacetals
e
w
ithLawes
e
son’sRea
g
s
ent h K. Nair, Ann Maria Jose, C. V. Asokan*
School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills P. O., Kottayam, 686 560, India
E-mail: asokancv@yahoo.com
Received 10 March 2004; revised 20 January 2005
thiolesters12 or b-keto dithioesters13 under solvolytic con-
ditions. A base induced demethylation of these building
blocks also gave the corresponding dithioesters14 and this
method was further extended to the synthesis of dihy-
drothiopyrans using alkenoyl ketene dithioacetals.15 We
now report that a-oxoketene dithioacetals can be efficient-
ly used for the preparation of a,b-unsaturated dithioesters
as well.
Abstract: The a-hydroxyketene dithioacetals 2 and 5, obtained
from a-oxoketene dithioacetals by the 1,2-reduction or the 1,2-ad-
dition of carbon nucleophiles, on treatment with Lawesson’s re-
agent afforded a,b-unsaturated dithioesters 3 and 6 in good yields.
Key words: ketene dithioacetals, dithiocarboxylates, Lawesson’s
reagent, thionation, heterodienes
The a-hydroxyketene dithioacetals 2a–e, derived from
aroyl ketene dithioacetals 1a–e, by a regioselective addi-
tion of sodium borohydride to the carbonyl group, on
treatment with Lawesson’s reagent (LR) gave the substi-
tuted dithiocinnamates 3a–e in high yields (Scheme 1).
The reaction was carried out with one equivalent of LR in
refluxing benzene for one hour. The isolated dithiocin-
namates underwent a slow dimerization involving a [4+2]
cycloaddition. However, the p-chloro-substituted dithio-
cinnamate 3c was found to be stable at room temperature
for several weeks. The ketene dithioacetal 1e prepared
from a-tetralone was also subjected to sodium borohy-
dride reduction and the resulting carbinol acetal was al-
lowed to react with LR under similar conditions. The
corresponding a,b-unsaturated dithioester 3e was isolated
in 87% yield (Scheme 1), which did not dimerize on keep-
ing at room temperature.
Synthetic methods for a,b-unsaturated dithioesters have
received considerable interest in view of their increased
reactivity, compared to their carboxylic analogues, as po-
tential dienes or dienophiles in hetero Diels–Alder cy-
cloadditions.1 Moreover, the cycloaddition products,
dihydrothiopyrans, are potential precursors of a wide
range of thioheterocycles with interesting biological prop-
erties.2 A recent report describes the synthesis of
phosphono-substituted dihydrothiopyrans using a-
phosphono-a,b-unsaturated dithioesters.3 There are very
few general methods available for the synthesis of a,b-un-
saturated dithioesters and those known are mostly specific
to certain substrate classes. The methods available in the
literature include (i) alkylation of thiolate anions obtained
by the addition of vinyl cuprates to carbon disulfide;4 (ii)
isomerization of g,d-unsaturated dithioesters;5 (iii) base-
catalyzed elimination of b-hydroxy dithioesters;6 and (iv)
Wittig–Horner, Peterson or Mukaiyama type condensa-
tion reactions of aldehydes and ketones.7 Hartke et al.
have also shown that a,b-unsaturated amides can be trans-
formed into the corresponding dithioesters by a sequence
of reactions involving thionation, alkylation and sulfhy-
drolysis.8 As part of our studies on the sulfhydrolysis of a-
oxoketene dithioacetals we have uncovered a general
method for the preparation of substituted a,b-unsaturated
dithioesters starting from readily available intermediates.
The vinylic protons of the a,b-unsaturated dithioesters 3
appear as doublets having a coupling constant of 15 Hz in
the 1H NMR spectra indicating that they exist in the E con-
figuration with the bulkier substituents at the b-position
trans to the dithioester group. The above sequence of re-
actions was carried out on acyl ketene dithioacetal 1f also.
We could isolate only the dimerized product 4 in 57%
yield from this reaction (Scheme 2). This is in accordance
with the literature report that methyl dithiocrotonate (3f)
undergoes facile dimerization to give 4 at room tempera-
ture.3
a-Oxoketene dithioacetals are highly versatile building
blocks in organic synthesis.9 The 1,2-reduction10a or 1,2-
addition of organomagnesium or lithium ragents10b,c to a-
oxoketene dithioacetals lead to the formation of a-hy-
droxyketene dithioacetals. Acid catalyzed partial hydrol-
ysis or solvolysis of these carbinols affords a,b-
unsaturated thioesters or esters respectively.10d,11 We have
recently developed several methods for the conversion of
a-oxoketene dithioacetals to the corresponding b-keto
a-Oxoketene dithioacetals 1 were also subjected to selec-
tive addition of carbon nucleophiles to the carbonyl group
and the allylic alcohols obtained were treated with LR.
This provides a method for the preparation of b-disubsti-
tuted a,b-unsaturated dithioesters. Thus the a-hydroxy-
ketene dithioacetals 5a–e obtained by the 1,2-addition of
methylmagnesium bromide on substituted ketene dithio-
acetals 1 were treated with LR for one hour. The corre-
sponding a,b-unsaturated dithioesters 6a–e were obtained
in good yields (Scheme 3). The ketene dithioacetal 1e de-
rived from a-tetralone on 1,2-addition of methyl magne-
SYNTHESIS 2005, No. 8, pp 1261–1264
x
x
.
x
x
.2
0
0
5
Advanced online publication: 07.04.2005
DOI: 10.1055/s-2005-865301; Art ID: T02804SS
© Georg Thieme Verlag Stuttgart · New York

1262
S. K. Nair et al.
PAPER
Scheme 3
Scheme 1
diates in organic synthesis and the method described here
sium bromide followed by treatment with LR gave 1-
methyl-3,4-dihydronaphthalene-2-carbodithioate (6d) in provides a valuable alternative to the previous methods
83% yield (Scheme 3). The a,b-unsaturated dithioesters for the synthesis of these compounds. Attempts to synthe-
6a–e, which are disubstituted at the b-position, are fairly size heterocycles of potential applications using the pre-
stable at room temperature and do not undergo any appre- pared a,b-unsaturated dithioesters are currently underway
ciable dimerization.
in our laboratory.
In most of the known methods7 of preparation of a,b-un-
saturated dithioesters 9 starting from carbonyl compound Melting points were determined using a Bristoline hot-stage micro-
scope and are uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on a Bruker WM 300 MHz NMR spectro-
meter in CDCl3 solution. Electron impact mass spectra were ob-
tained on a Finnigan-MAT 312 spectrometer. Elemental analyses
7, the dithioester functionality is introduced along with
the a-methylene group to form 8. The present method pro-
vides an opportunity to introduce dithioester functionality
at the a position of the carbonyl group of the starting ke-
tone to afford 9 (Scheme 4).
were done on an Elementar Vario EL III Carlo Erba 1108 instru-
ment. Column chromatography was performed on silica gel (60–
120 mesh). All reactions were carried out in an efficient chemical
fume hood in benzene (Caution! carcinogenic) under N2 and in
flame dried glassware. a-Oxoketene dithioacetals 1 were prepared
following reported procedures.9
In conclusion, we have developed a facile two step pro-
cess for the conversion of a-oxoketene dithioacetals to
a,b-unsaturated dithioesters, which are valuable interme-
S
O
SCH3
SCH3
S
1) NaBH4/EtOH
2) LR/C6H6
SMe
H3C
Wittig-Horner
H3C
SCH3
R1
Peterson, etc.
O
R2
1f
3f
R1
8
R2
R
S
H3CS
S
CH3
via ketene
7
R1
SMe
dithioacetal
CS2CH3
R2
CH3
4
9
Scheme 2
Scheme 4
Synthesis 2005, No. 8, 1261–1264 © Thieme Stuttgart · New York

PAPER
Reactions of a-Hydroxyketene Dithioacetals with Lawesson’s Reagent
1263
a,b-Unsaturated Dithioesters 3; General Procedure
Methyl 2,4-Dimethyl-6-methylthio-2H-3,4-dihydrothiopyran-
dithiocarboxylate (4)
Yield: 710 mg (57%); red viscous liquid.
Spectral data have been previously reported.3
NaBH4 (30 mmol, 0.72 g) was taken in absolute EtOH (30 mL). a-
Oxoketene dithioacetal 1 (10 mmol) was added and the mixture was
refluxed for 1 h. The contents were poured into cold aq sat. solution
of NH4Cl (100 mL). The mixture was extracted with CHCl3 (3 × 30
mL), dried and concentrated. The crude carbinol acetal 2 obtained
was taken in benzene (50 mL) and to this solution was added LR (10
mmol, 4.04 g). The mixture was refluxed for 1 h, cooled and fil-
tered. The benzene was removed under vacuum and the crude
dithioester was purified by flash column chromatography over sili-
ca gel using hexanes as the eluent.
a,b-Unsaturated Dithioesters 6; General Procedure
To a well-cooled (0–5 °C) solution of methylmagnesium bromide
(15 mmol) in anhyd Et2O, was added ketene dithioacetal 1 (10
mmol) in Et2O (50 mL) slowly over 15 min. The mixture was stirred
at this temperature for half an hour and was poured into cold aq sat.
NH4Cl solution (100 mL) and extracted with Et2O (3 × 50 mL). The
combined organic layers were washed with H2O and dried. Et2O
was removed and the crude carbinol acetal 5 was taken in benzene16
(50 mL) and to this solution was added Lawesson’s Reagent (4.04
g, 10mmol). The mixture was refluxed for 1 h with stirring. After
the reaction, the mixture was cooled and was filtered. The filtrate
was washed with H2O, dried and concentrated. The crude
dithioester was purified by column chromatography over silica gel
using hexanes as the eluent.
Methyl (E)-3-Phenylprop-2-enedithioate (3a)
Yield: 1.18 g (61%); red viscous liquid.
Spectral data have been previously reported.8
Methyl (E)-3-(4-Methylphenyl)prop-2-enedithioiate (3b)
Yield: 1.41 g (68%); red viscous liquid.
IR (neat): 1595, 1510, 1415, 1035, 950 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 3 H), 2.69 (s, 3 H), 7.17
(d, 2 H, J = 9 Hz), 7.37 (d, 1 H, J = 15 Hz), 7.45 (d, 2 H, J = 9 Hz),
7.74 (d, 1 H, J = 15 Hz).
13C NMR (75 MHz, CDCl3): d = 18.7, 21.2, 124.6, 128.3, 128.7,
129.4, 132.1, 137.5, 223.6 (C=S).
Methyl (E)-3-Phenyl-3-methylprop-2-enedithioate (6a)
Yield: 1.27 g (61%); red viscous liquid.
IR (neat): 1590, 1565, 1440, 1220, 1020, 910 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H), 2.55 (s, 3 H), 6.97
(s, 1 H), 7.13–7.25 (m, 3 H), 7.34–7.45 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 19.5, 28.6, 126.50, 128.4, 128.7,
132.6, 143.1, 147.7, 225.0.
Anal. Calcd for C11H12S2: C, 63.41; H, 5.81. Found: C, 63.28; H,
5.61.
Methyl (E)-3-(4-Chlorophenyl)prop-2-enedithioate (3c)
Yield: 1.41 g (81%); red needles; mp 77–79 °C.
Anal. Calcd for C11H12S2: C, 63.41; H, 5.81. Found: C, 63.70; H,
5.82.
IR (KBr): 1580, 1485, 1410, 1195, 1010, 940 cm–1.
Methyl (E)-3-(4-Methylphenyl)-3-methylprop-2-enedithioate
(6b)
Yield: 1.38 g (62%); red viscous liquid.
IR (neat): 1585, 1550, 1505, 1440, 1210, 1020, 910 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H), 2.57 (s, 3 H), 2.66
(s, 3 H), 7.10 (s, 1 H), 7.16 (d, 2 H, J = 8.5 Hz), 7.42 (d, 2 H, J = 8.5
Hz).
1H NMR (300 MHz, CDCl3): d = 2.70 (s, 3 H), 7.26 (d, 1 H, J = 8.5
Hz), 7.32 (d, 1 H, J = 15 Hz), 7.44 (d, 2 H, J = 8.5 Hz), 7.64 (d, 1
H, J = 15 Hz).
13C NMR (75 MHz, CDCl3): d = 19.2, 129.3, 129.6, 133.3, 136.1,
223.1.
EIMS: m/z (%) = 228 (M+, 28.7), 181 (100), 145 (20.3).
13C NMR (75 MHz, CDCl3): d = 19.7, 21.2, 125.7, 126.4, 129.5,
132.0, 138.9, 148.0, 224.9.
Anal. Calcd for C10H9ClS2: C, 52.50; H, 3.97. Found: C, 52.54; H,
3.76.
Anal. Calcd for C12H14S2: C, 64.82; H, 6.35. Found: C, 64.86; H,
6.41.
Methyl (E)-3-(4-Bromophenyl)prop-2-enedithioate (3d)
Yield: 1.86 g (68%); red viscous liquid.
IR (KBr): 1585, 1560, 1480, 1250, 1000 cm–1.
Methyl (E)-3-(4-Bromophenyl)-3-methylprop-2-enedithioate
1H NMR (300 MHz, CDCl3): d = 2.74 (s, 3 H), 7.38 (d, 1 H, J = 15
Hz), 7.44 (d, 2 H, J = 8.7 Hz), 7.50 (d, 2 H, J = 8.7 Hz), 7.70 (d, 1
H, J = 15 Hz).
13C NMR (75 MHz, CDCl3): d = 19.2, 124.4, 129.7, 133.3, 133.7,
136.1, 223.0.
(6c)
Yield: 1.92 g (67%); red viscous liquid.
IR (neat): 1580, 1480, 1210, 1005 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 2.65 (s, 3 H), 6.98
(s, 1 H), 7.35 (d, 2 H, J = 9 Hz), 7.47 (d, 2 H, J = 9 Hz).
13C NMR (75 MHz, CDCl3): d = 19.5, 29.7, 125.8, 128.1, 129.55,
131.6, 132.7, 145.8, 224.9.
Anal. Calcd for C10H9BrS2: C, 43.96; H, 3.32. Found: C, 43.90; H,
3.76.
Anal. Calcd For C11H11BrS2: C, 46.00; H, 3.86. Found: C, 45.86; H,
3.76.
Methyl 3,4-Dihydronaphthalene-2-carbodithioate (3e)
Yield: 1.91 g (87%); red viscous liquid.
IR (KBr): 1595, 1550, 1445, 1170, 1055 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.66 (s, 3 H), 2.83–2.88 (m, 2 H),
2.95–3.00 (m, 2 H), 7.13–7.26 (m, 4 H), 7.59 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.8, 28.1, 28.6, 127.3, 128.0,
129.7, 130.0, 130.8, 133.4, 137.9, 144.5, 227.6.
Methyl 1-Methyl-3,4-dihydronaphthalene-2-carbodithioate
(6d)
Yield: 1.94 g (83%); red needles; mp 58–59 °C.
IR (KBr): 1595, 1480, 1445, 1280, 1095, 1040 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H), 2.81–2.89 (m, 2 H),
2.93 (s, 3 H), 3.08–3.15 (m, 2 H, 7.38–7.51 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 15.9, 20.3, 29.1, 30.7, 124.4, 127.0,
127.8, 127.9, 128.0, 135.9, 136.2, 143.4, 237.2.
Anal. Calcd for C12H12S2: C, 65.41; H, 5.49. Found: C, 65.18; H,
5.35.
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1264
S. K. Nair et al.
PAPER
(3) Al-Badri, H.; Collignon, N.; Maddaluno, J.; Masson, S.
EIMS: m/z = 234 (M+, 20.5), 187 (59.6), 128 (37.7), 115 (40.2).
Tetrahedron 2000, 56, 3909.
(4) Westmijze, H.; Kleijn, H.; Miejer, J.; Vermeer, P. Synthesis
1979, 432.
Anal. Calcd for C13H14S2: C, 66.62; H, 6.02. Found: C, 67.00; H,
6.02.
(5) Gosselin, P.; Masson, S.; Thuillier, A. Tetrahedron Lett.
1980, 21, 2421.
(6) (a) Masson, S.; Thuillier, A. Tetrahedron Lett. 1982, 23,
4087. (b) Rettberg, N.; Wagner, U.; Hartke, K. Arch. Pharm.
(Weinheim, Ger.) 1993, 326, 977. (c) Lawson, K. R.;
Singleton, A.; Whitham, G. H. J. Chem. Soc., Perkin Trans.
1 1984, 859.
(7) Hartke, K.; Kunze, O. Liebigs Ann. Chem. 1989, 321.
(8) Hoffman, R.; Hartke, K. Chem. Ber. 1980, 113, 919.
(9) (a) Dieter, R. K. Tetrahedron 1986, 42, 3029. (b) Junjappa,
H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423.
(c) Kolb, M. Synthesis 1990, 171.
Methyl 3-Methylbut-2-enedithioate (6e)
Yield: 920 mg (63%); red viscous liquid.
IR (neat): 1610, 1440, 1420, 1240, 1180, 1020 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.90 (s, 3 H), 2.18 (s, 3 H), 2.55
(s, 3 H), 6.67 (s 1 H).
13C NMR (75 MHz, CDCl3): d = 18.9, 21.6, 29.2, 131.5, 148.4,
225.8.
Anal. Calcd for C6H10S2: C, 49.27; H, 6.89. Found: C, 49.58; H,
6.98.
(10) (a) Saquet, M.; Thuillier, A. Bull. Soc. Chim. Fr. 1966,
3969. (b) Dieter, R. K.; Jenkitkasemwong, Y.; Dieter, L. W.
J. Org. Chem. 1984, 49, 3183. (c) Dieter, R. K.;
Jenkitkasemwong, Y. Tetrahedron Lett. 1982, 23, 3747.
(d) Myrboh, B.; Ila, H.; Junjappa, H. J. Org. Chem. 1983, 48,
5327.
(11) (a) Myrboh, B.; Asokan, C. V.; Ila, H.; Junjappa, H.
Synthesis 1984, 50. (b) Asokan, C. V.; Ila, H.; Junjappa, H.
Synthesis 1985, 163. (c) Singh, G.; Purkayastha, M. L.; Ila,
H.; Junjappa, H. J. Chem. Soc., Perkin Trans. 1 1985, 1289.
(d) Dieter, R. K.; Dieter, J. W. J. Chem. Soc., Chem.
Commun. 1983, 1378.
Aknowledgment
This work was supported by the Kerala State CSTE foundation.
SKN and ANJ thank UGC and MG University for research fel-
lowships respectively. We are grateful to Dr. Prakash Chandran
(POSTECH, South Korea) and Professor S. Perumal (Madurai
Kamaraj University) for providing spectral and analytical data.
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Synthesis 2005, No. 8, 1261–1264 © Thieme Stuttgart · New York